Cortical excitability in cocaine-dependent patients: a replication and extension of TMS findings

Cortical excitability can be assessed by transcranial magnetic stimulation (TMS). Previously we observed that TMS motor threshold (MT) was elevated in abstinent cocaine-dependent subjects. In the current study we aimed at replicating our initial finding, exploring other TMS-based measures of excitability, and examining association with personality characteristics. Nineteen cocaine-dependent and 12 healthy control subjects were examined. Resting and activated motor thresholds (RMT and AMT) and duration of the cortical silent period (CSP) were examined. The Cocaine Experience Questionnaire (CEQ) was administered to assess cocaine-induced psychotic symptoms. The relationship between Minnesota Multiphasic Personality Inventory (MMPI) scales and cortical excitability measures was also examined. AMT was significantly elevated in cocaine-dependent subjects on both hemispheres. RMT was also significantly elevated on the right hemisphere. No CSP changes were noted. Patients with cocaine-induced paranoia had longer CSPs on the right hemisphere compared to subjects reporting no paranoid experiences. The patients displayed significantly elevated scores on several MMPI scales, though the scale scores did not correlate with cortical excitability measures. These data support our initial finding of decreased cortical excitability in abstinent cocaine-dependent subjects. We interpret this finding as a compensatory mechanism against the stimulating and epileptogenic effects of cocaine.     

Dysbalance of cortical inhibition and excitation in abstinent cocaine-dependent patients

The effects of chronic cocaine dependence on cortical inhibitory/excitatory processes are not well characterized. Employing transcranial magnetic stimulation measures of motor cortical excitability, we have previously reported an elevation of motor threshold (MT) suggesting reduced excitability and an increased long-interval intracortical facilitation (LICF) suggesting increased excitability. In the current study, we used an expanded battery of TMS cortical excitability measures to further examine motor cortex excitability in a larger sample of well-characterized and closely monitored for drug use, abstinent cocaine-dependent subjects (N = 52) and healthy controls (N = 42). Furthermore, coil-to-cortex distance was assessed in a subsample of both groups. We verified that long-interval intracortical facilitation (LICF), possibly representing glutamatergic cortical neurotransmission, was significantly increased in cocaine-dependent patients. Significantly longer cortical silent periods (CSP) and elevated MT were also observed while there was no significant abnormality in long-interval intracortical inhibition (LICI). Increased LICF and CSP duration suggest increased cortical excitability and increased inhibition, respectively, of different neurotransmitter systems in cocaine-dependent patients. Increased MT might reflect an adaptation to those effects of cocaine abuse that enhance cortical excitability. Overall, the data point to the complex nature of chronic cocaine dependence on the balance of cortical inhibitory/excitatory mechanisms.     

Reduced excitability of the motor cortex in untreated patients with de novo idiopathic "grand mal" seizures.

OBJECTIVES: Transcranial magnetic stimulation (TMS) was used to investigate motor cortex excitability, intracortical excitatory, and inhibitory pathways in 18 patients having experienced a first "grand mal" seizure within 48 hours of the electrophysiological test. All had normal brain MRI, and were free of any treatment, drug, or alcohol misuse. Results were compared with those of 35 age matched normal volunteers. METHODS: The following parameters of responses to TMS were measured: motor thresholds at rest and with voluntary contraction, amplitudes of responses, cortical silent periods, and responses to paired pulse stimulation with interstimulus intervals of 1 to 20 ms. RESULTS: In patients, there were significantly increased motor thresholds with normal amplitudes of motor evoked potentials (MEPs), suggesting decreased cortical excitability. Cortical silent periods were not significantly different from those of normal subjects. Paired TMS with short interstimulus intervals (1-5 ms) induced normal inhibition of test MEPs, suggesting preserved function of GABAergic intracortical inhibitory interneurons. On the contrary, the subsequent period of MEP facilitation found in normal subjects (ISIs of 6-20 ms) was markedly reduced in patients. This suggests the existence of abnormally prolonged intracortical inhibition or deficient intracortical excitation. In nine patients retested 2 to 4 weeks after the initial seizure, these abnormalities persisted, although to a lesser extent. CONCLUSION: The present findings together with abnormally high motor thresholds could represent protective mechanisms against the spread or recurrence of seizures.     

Dissociation, hemispheric asymmetry, and dysfunction of hemispheric interaction: a transcranial magnetic stimulation approach

The authors investigated the hypothesis that dissociation may represent a functional dysconnectivity syndrome using a transcranial magnetic stimulation (TMS) approach. Transcranial magnetic stimulation investigations that included motor thresholds and the transcallosal conduction time (TCT) reflecting the interhemispheric transfer were performed in 74 right-handed students. All subjects completed the Dissociative Experience Scale. The high dissociators had a significantly lower left hemispheric excitability than right hemispheric excitability. They also had a significantly shorter TCT from the left to the right hemisphere than did the low dissociators. These results suggest that the neural basis of dissociation may involve a cortical asymmetry with a left hemispheric superiority or, alternatively, a lack of right hemispheric integration.     

Influence of task-related ipsilateral hand movement on motor cortex excitability.

OBJECTIVE: The time course of the right motor cortex excitability in relation to a task-related voluntary right thumb twitch was studied using sub-threshold transcranial magnetic stimulation (TMS) to the right motor cortex. METHODS: Motor excitability was studied in 8 adult subjects who made a brief right thumb twitch to the predictable omission of every fifth tone in a series of tones 2.5 s apart. This paradigm avoided an overt sensory cue, while allowing experimental control of TMS timing relative to both movement and the cue to move. Motor excitability was characterized by several measures of motor evoked potentials (MEPs) recorded from the left thenar eminence in response to TMS over the right scalp with a 9 cm coil: probability of eliciting MEPs, incidence of MEPs and amplitude of MEPs. RESULTS: All subjects showed suppression of motor excitability immediately following a voluntary right thumb twitch (ipsilateral response), and up to 1 s after it. However, two distinctly different effects on motor excitability were observed before the response: two subjects showed excitation, beginning about 500 ms before response until 300 ms after it, followed by the post-movement suppression; 6 subjects displayed pre-movement suppression, beginning about 600 ms before the response and persisting for the duration. CONCLUSIONS: The net effect of an ipsilateral response on motor cortex can be either inhibitory or excitatory, changing with time relative to the response. These findings are compatible with two separate processes, inhibitory and excitatory, which interact to determine motor excitability ipsilateral to the responding hand.     

Changes of cortical excitability of human motor cortex in spinocerebellar ataxia type 2. A study with paired transcranial magnetic stimulation

The aim of this study was to evaluate motor cortex excitability in spinocerebellar ataxia type 2 (SCA2). Cortical silent period (CSP), motor thresholds, and intracortical inhibition and facilitation by paired transcranial magnetic stimulation (TMS) were investigated in 18 SCA2 patients and in 20 controls. The mean CSP duration and motor threshold after TMS were significantly increased in the patient group. Intracortical inhibition by paired TMS at short interstimulus intervals (ISIs) showed no significant differences between patients and controls; at longer ISIs, the expected facilitation of test responses, observed in control subjects, resulted significantly less marked in SCA2 patients at all the tested intervals. Our findings extend previous findings on cerebellar dysfunctions of varying aetiologies by investigating intracortical excitability in SCA2. In addition, this study demonstrates that the cortical excitability involvement found in SCA2 is independent on the cytosine-adenine-guanine repeat expansion. The neurophysiological alterations seen in our patients relate to the worsening of general clinical condition. Thus, we might speculate that changes of motor cortex excitability in SCA2 represent a slow neurodegenerative process characterized by gradual loss of cerebellar neurons leading to an increasing disturbance of the balance between inhibitory and excitatory circuits in the motor system.     

Motor and phosphene thresholds: a transcranial magnetic stimulation correlation study

Objective: To investigate the stability of visual phosphene thresholds and to assess whether they correlate with motor thresholds. Background: Currently, motor threshold is used as an index of cortical sensitivity so that in transcranial magnetic stimulation (TMS) experiments, intensity can be set at a given percentage of this value. It is not known whether this is a reasonable index of cortical sensitivity in non-motor and hence whether it should be used in experiments where other cortical areas are targeted. Previous studies have indicated that phosphene threshold might be a suitable alternative in TMS studies of the visual system. Method: Using single pulse TMS visual phosphene and motor thresholds were measured in 15 subjects. Both thresholds were retested in seven of these subjects a week later. Result: Visual phosphene thresholds, though stable within subjects across the two sessions, showed greater variability than motor thresholds. There was no correlation between the two measures. Conclusion: TMS motor thresholds cannot be assumed to be a guide to visual cortex excitability and by extension are probably an inappropriate guide to the cortical excitability of other non-motor areas of the brain. Phosphene thresholds are proposed as a potential standard for inter-individual comparison in visual TMS experiments.     

Functional involvement of cerebral cortex in human narcolepsy

Abstract The pathophysiology of human narcolepsy is still poorly understood. The hypoactivity of some neurotransmitter systems has been hypothesised on the basis of the canine model. To determine whether narcolepsy is associated with changes in excitability of the cerebral cortex, we assessed the excitability of the motor cortex with transcranial magnetic stimulation (TMS) in 13 patients with narcolepsy and in 12 control subjects. We used several TMS paradigms that can provide information on the excitability of the motor cortex. Resting and active motor thresholds were higher in narcoleptic patients than in controls and intracortical inhibition was more pronounced in narcoleptic patients. No changes in the other evaluated measures were detected. These results are consistent with an impaired balance between excitatory and inhibitory intracortical circuits in narcolepsy that leads to cortical hypoexcitability. We hypothesise that the deficiency of the excitatory hypocretin/orexin-neurotransmitter-system in narcolepsy is reflected in changes of cortical excitability since circuits originating in the lateral hypothalamus and in the basal forebrain project widely to the neocortex, including motor cortex. This abnormal excitability of cortical networks could be the physiological correlate of excessive daytime sleepiness and it could be the substrate for allowing dissociated states of wakefulness and sleep to emerge suddenly while patients are awake, which constitute the symptoms of narcolepsy.     

Inter-hemispheric asymmetry of motor corticospinal excitability in major depression studied by transcranial magnetic stimulation

BACKGROUND: Imaging and electroencephalographic studies have reported inter-hemispheric asymmetries in frontal cortical regions associated with depression. This study aimed at comparing motor corticospinal excitability assessed by methods of transcranial magnetic stimulation (TMS) between the right and left hemispheres in patients with major depression and healthy controls. METHOD: Patients with major depression (n=35) and healthy controls (n=35) underwent a bilateral study of various motor corticospinal excitability parameters, including rest motor threshold (RMT), corticospinal silent period (CSP) duration and intra-cortical inhibition (ICI) and facilitation (ICF). Indexes of asymmetry were calculated, and the relationships between excitability parameters and clinical scores of depression were statistically analyzed. RESULTS: Depressed patients showed a reduced excitability of both excitatory (RMT, ICF) and inhibitory (CSP, ICI) processes in the left hemisphere, compared to the right hemisphere and to healthy controls. CONCLUSION: The present results confirmed the existence of inter-hemispheric asymmetries in frontal cortex activities of depressed patients in favor of a left-sided reduced excitability. This neurophysiological approach may help to guide repetitive TMS procedures in the treatment of depressive disorders.     

Cortical excitability and age-related volumetric MRI changes.

OBJECTIVE: Normative data on transcranial magnetic stimulation (TMS)-derived measures of cortical excitability in the elderly is sparse. Nevertheless, elderly subjects are included as controls in studies utilizing TMS to investigate disease states. Age-associated increased ventricular cerebrospinal fluid CSF (vCSF) and white matter hyperintensity (WMH) MRI volumes have uncertain significance in non-demented elderly. Information regarding cortical excitability in neurologically intact elderly would augment our understanding of the pathophysiology of aging and assist in the interpretation of TMS studies involving elderly subjects. METHODS: Twenty-four healthy elderly subjects underwent TMS testing to determine outcomes of resting motor threshold (RMT) cortical silent period (cSP) and central motor conduction time for examination in relation to WMH, vCSF, and CNS volumes. RESULTS: Increased vCSF and WMH volumes were associated with decreased right and left hemisphere RMT. Smaller CNS volumes were associated with decreased right hemisphere RMT and shorted cSP. CONCLUSIONS: Commonly observed age-associated MRI changes are associated with findings consistent with increased cortical excitability. SIGNIFICANCE: Age-related MRI findings likely reflect changes at a cellular level, and may influence cognitive and motor integrity in the elderly. Future TMS studies investigating cortical excitability may wish to consider neuroimaging markers of neurodegeneration prior to enrolling elderly subjects as controls.     

Cortical inhibition and excitation in abstinent cocaine-dependent patients: a transcranial magnetic stimulation study

Prior transcranial magnetic stimulation studies showed that resting motor threshold is elevated in abstinent cocaine-dependent patients, suggesting a decrease in axonal excitability. In contrast, the increased incidence of seizures and psychosis in this group suggests increased excitability or decreased inhibition. Here, we studied long-interval intracortical facilitation and long-interval intracortical inhibition, paired-pulse transcranial magnetic stimulation measures that are more directly linked to glutamatergic cortical facilitation and GABAergic inhibition, respectively. Ten cocaine-dependent and 10 healthy controls were examined. Resting motor threshold, long-interval intracortical facilitation and long-interval intracortical inhibition were tested from the left motor cortex. The cocaine group showed an elevated resting motor threshold and an increased long-interval intracortical facilitation, whereas long-interval intracortical inhibition was normal. Although the increase in long-interval intracortical facilitation suggests exaggerated cortical glutamatergic excitability, the increase in resting motor threshold may signify a protective mechanism against seizures and psychosis.     

Inter- and intra-individual variability of paired-pulse curves with transcranial magnetic stimulation (TMS).

OBJECTIVES: Previous studies have evaluated the variability of motor thresholds (MTs) and amplitude of motor-evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) within and across individuals. Here we evaluate the reproducibility and inter-hemispheric variability of measures of cortical excitability using the 'conventional' paired-pulse (PP) TMS technique. METHODS: We studied PP curves of the left and right hemisphere in 10 healthy subjects on two separate days 2 weeks apart. The inter-stimulus intervals studied were 1, 3, 6, 8, 10 and 12 ms with the conditioning stimulus being 80% of the resting MT, and a single test stimulus producing MEPs of approximately 0.8 mV peak-to-peak amplitude. RESULTS: As a group, the PP curves of the left and right hemispheres, and of Day 1 and Day 2 were not significantly different. The intracortical inhibition (ICI), but not the intracortical facilitation, showed a good correlation across days within the individuals. CONCLUSIONS: Cortical excitability, particularly ICI, measured by PP TMS shows no inter-hemispheric asymmetry and is reproducible within individuals.     

Motor cortical excitability studied with repetitive transcranial magnetic stimulation in patients with Huntington's disease.

OBJECTIVE: TMS techniques have provided controversial information on motor cortical function in Huntington's disease (HD). We investigated the excitability of motor cortex in patients with HD using repetitive transcranial magnetic stimulation (rTMS). METHODS: Eleven patients with HD, and 11 age-matched healthy subjects participated in the study. The clinical features of patients with HD were evaluated with the United Huntington's Disease Rating Scale (UHDRS). rTMS was delivered with a Magstim Repetitive Magnetic Stimulator through a figure-of-8 coil placed over the motor area of the first dorsal interosseus (FDI) muscle. Trains of 10 stimuli were delivered at 5 Hz frequency and suprathreshold intensity (120% resting motor threshold) with the subjects at rest and during voluntary contraction of the target muscle. RESULTS: In healthy subjects at rest, rTMS produced motor evoked potentials (MEPs) that increased in amplitude over the course of the trains. Conversely in patients, rTMS left the MEP size almost unchanged. In both groups, during voluntary contraction rTMS increased the silent period (SP) duration. CONCLUSIONS: Because rTMS modulates motor cortical excitability by activating cortical excitatory and inhibitory interneurons these findings suggest that in patients with HD the excitability of facilitatory intracortical interneurones is decreased. SIGNIFICANCE: We suggest that depressed excitability of the motor cortex in patients with HD reflects a disease-related weakening of cortical facilitatory mechanisms.     

Changing cortical excitability with low-frequency transcranial magnetic stimulation can induce sustained disruption of tactile perception.

Transcranial magnetic stimulation (TMS) is promising as a therapeutic tool, and TMS of the motor system has served as a model for regionally specific modulations of cortical excitability. It is unclear, however, to what extent response characteristics of the motor cortex are representative of other brain systems. We wanted to determine whether TMS could induce a sustained disruption of somatosensory processing beyond the stimulation duration, similar to observations in the motor system. We applied 1-Hz TMS at 110% of subjects' motor thresholds for a variable duration over the right and left somatosensory cortex before subjects performed a tactile frequency discrimination task with the left hand. Tactile discrimination was impaired only after TMS over the right somatosensory cortex (analysis of variance: p <.01). The duration of this impairment correlated with the duration of the preceding TMS; the effect lasted approximately 2 min after 5 min of TMS, 4 min after 10 min of TMS, and 8 min after 20 min of TMS. Two conclusions arise: 1) low-frequency TMS can interfere with tactile perception in a robust and sustained way, and 2) TMS dosing parameters effective in the motor system are also effective in the somatosensory system and may reflect a modality-independent response characteristic of the cerebral cortex.     

Effects of low frequency and low intensity repetitive paired pulse stimulation of the primary motor cortex.

OBJECTIVE: Following a previous report [Bestmann et al. Clin Neurophysiol 2004;115:755-64] that pairs of subthreshold pulses of transcranial magnetic stimulation (TMS) can show temporal summation, we explored whether repeated application of pairs of stimulation could produce long-lasting after effects on the excitability of the human motor cortex. METHODS: Twelve healthy subjects received 25 min repetitive paired pulse magnetic stimulation (paired rTMS) given at a frequency of about 0.6 Hz over the left primary motor cortex (500 paired stimuli in total). The interval between the paired stimuli was 3 ms and the intensity of both stimuli was 80% of active motor threshold. The resting and active motor threshold, MEP recruitment curve, short interval intracortical inhibition (SICI) and facilitation, and the duration of the cortical silent period (SP) were tested for the right first interosseous muscle (FDI) before and two times after the end of 25 min paired rTMS. RESULTS: Prolonged subthreshold paired rTMS produced a significant decrease in excitability in the corticospinal projection to FDI: resting motor threshold was significantly increased and MEP recruitment was significantly decreased, SICI was significantly increased at 2 and 4 ms and the SP was significantly increased in duration. CONCLUSIONS: Prolonged low frequency paired rTMS at subthreshold intensity can modulate cortical excitability by producing inhibitory effects that outlast the period of stimulation.     

Motor cortical excitability in schizophrenia.

BACKGROUND: Transcranial magnetic stimulation (TMS) provides a method to examine cortico-cortical motor excitability and hemispheric asymmetry in unmedicated and medicated schizophrenia patients. METHODS: Fourteen right-handed schizophrenia patients (seven on conventional neuroleptics and seven medication-free) were compared with seven right-handed, age- and gender-matched normal control subjects. Motor threshold for induction of motor-evoked potentials (MEPs) and bihemispheric intracortical inhibition and facilitation were measured with single-pulse and paired-pulse TMS. RESULTS: Medicated patients showed an approximately 5% higher motor thresholds in both hemispheres than unmedicated patients and control subjects. Normal control subjects had a nearly 10% higher threshold for the left than the right hemisphere, whereas the opposite was true for the patient groups (5-10% higher threshold on the right than the left). Medicated patients showed significantly decreased intracortical inhibition relative to unmedicated patients and control subjects. This difference was more pronounced for the right than for the left hemisphere. CONCLUSIONS: Treatment with conventional neuroleptics is associated with increased motor threshold and decreased intracortical inhibition, whereas unmedicated patients did not differ from normal control subjects on these measures; however, schizophrenia may be characterized by a reversed pattern of interhemispheric corticospinal excitability.     

No correlation between moving phosphene and motor thresholds: a transcranial magnetic stimulation study

The aim of this study was to investigate the temporal stability of moving phosphenes and to assess whether moving phosphene thresholds (PTs) correlate with motor thresholds (MTs). Small moving sensations, so-called moving phosphenes, are perceived when V5, an area important for visual motion analysis, is stimulated by transcranial magnetic stimulation (TMS). However, it is still a matter of debate if V5 phosphenes are stable sensations across measurements and if they are a reasonable index of the cortical excitability of V5. Currently, MT is more commonly used as an index of global cortical excitability. However, previous studies have indicated that stationary PTs are suitable alternatives when the primary visual cortex is stimulated by TMS. Using paired-pulse TMS, stationary and moving PTs and applying single pulse TMS, MTs were measured in 11 subjects. PTs were retested in nine subjects 5-7 days later. Stationary and moving PTs were stable within subjects across the two sessions and showed a high inter-correlation. Conversely, PTs and MTs did not correlate. Our results are in agreement with previous studies showing that excitatory measurements of one specific cortex cannot be generalized to the excitability of the whole cortex. Thus, we propose specific measures for cortices of interest: PT for visual experiments and MT for motor experiments.     

Time course of motor excitability before and after a task-related movement.

AIMS OF THE STUDY: The time course of motor excitability during a task-related unilateral right thumb movement was studied using sub-threshold transcranial magnetic stimulation (TMS) to the contralateral left motor cortex. The level of stimulation evoked a motor evoked potential (MEP) in the thumb when the subject was at rest in approximately 10% of the trials. METHODS: Subjects made a brief right thumb movement to the predictable omission of regularly presented tone bursts allowing experimental definition of TMS relative to the cue to move. Motor cortical excitability was characterized by amplitude and/or probability of eliciting MEPs. RESULTS: There were four periods of altered motor excitability during task performance compared to a control resting state: a first period of weak facilitation before movement between -500 to -200 ms, a second period without increased excitability approximately 150 ms before movement onset when MEPs amplitude was below that seen in rest, a third period of strong facilitation between -100 ms before movement and +200 ms after facilitation and a fourth period of weak facilitation between +200 to +500 ms. CONCLUSION: These results show that during performance of a task requiring a motor response, motor cortical excitability is increased above resting for hundreds of millisecond before and after the response, except for a transient period between 75 and 150 ms prior to movement onset. The temporal pattern of these excitability changes is compatible with multiple excitatory and inhibitory inputs interacting on motor cortex.     

Event-related desynchronization and excitability of the ipsilateral motor cortex during simple self-paced finger movements.

OBJECTIVE: To study the time course of oscillatory EEG activity and corticospinal excitability of the ipsilateral primary motor cortex (iM1) during self-paced phasic extension movements of fingers II-V. METHODS: We designed an experiment in which cortical activation, measured by spectral-power analysis of 28-channel EEG, and cortical excitability, measured by transcranial magnetic stimulation (TMS), were assessed during phasic self-paced extensions of the right fingers II-V in 28 right-handed subjects. TMS was delivered to iM1 0-1500 ms after movement onset. RESULTS: Ipsilateral event-related desynchronization (ERD) during finger movement was paralleled by increased cortical excitability of iM1 from 0-200 ms after movement onset and by increased intracortical facilitation (ICF) without changes in intracortical inhibition (ICI) or peripheral measures (F waves). TMS during periods of post-movement event-related synchronization (ERS) revealed no significant changes in cortical excitability in iM1. CONCLUSIONS: Our findings indicate that motor cortical ERD ipsilateral to the movement is associated with increased corticospinal excitability, while ERS is coupled with its removal. These data are compatible with the concept that iM1 contributes actively to motor control. No evidence for inhibitory modulation of iM1 was detected in association with self-paced phasic finger movements. SIGNIFICANCE: Understanding the physiological role of iM1 in motor control.     

Does the recruitment of excitation and inhibition in the motor cortex differ?

The level of excitability within the motor cortex can be described as a balance between excitation and inhibition, but it is unknown how well both processes correlate. To address this question, the authors measured motor cortical excitability and inhibition in healthy human subjects, comparing the recruitment of motor evoked potentials (MEPs) and the duration of the cortical silent period (CSP) after transcranial magnetic stimulation (TMS). Single-pulse "focal" TMS was applied at intensities varying between 90% and 200% of motor thresholds to the right motor cortex of 15 healthy volunteers. The peak-to peak size of MEP responses and the duration of the CSP were measured in small hand muscles. Stimulus-response (S-R) curves were constructed by plotting the MEP size and CSP duration against stimulus intensities. The absolute duration of CSP and the size MEPs correlated significantly and to a similar extent with stimulus intensity (r = 0.60 and 0.53, respectively). The slope of the MEP-S-R was steeper compared with CSP-S-R, particularly at low stimulation intensities. CSP duration saturated earlier and CSP-S-Rs were shifted upwards at a given stimulus intensity compared with MEP-S-Rs. The findings suggest that recruitment of inhibition and excitation within the sensorimotor cortex correlate. However, inhibitory effects are recruited at lower intensities and saturate earlier than excitation.